Crystalline Chemotherapeutic

ABSTRACT

N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea Crystalline Form 2, ways to make it, formulations comprising it and made with it and methods of treating patients having disease using it are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/981,265, filed Oct. 19, 2007 and hereby incorporated by reference inits entirety.

FIELD OF THE INVENTION

This invention pertains toN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2, ways to make it, formulations comprising it and madewith it and methods of treating patients having disease using it.

BACKGROUND OF THE INVENTION

N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea(ABT-869) belongs to a family of protein tyrosine kinases (PTKs) whichcatalyze the phosphorylation of specific tyrosine residues in cellularproteins. Aberrant or excessive PTK activity has been observed in manydisease states including benign and malignant proliferative disordersand diseases resulting from inappropriate activation of the immunesystem.

Crystallinity of ABT-869 may effect, among other physical and mechanicalproperties, their stability, solubility, dissolution rate, hardness,compressibility and melting point. Because ease of manufacture andformulation of ABT-869 is dependent on some, if not all, of theseproperties, there is an existing need in the chemical and therapeuticarts for identification of crystalline forms of ABT-869 and ways toreproducibly make them.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains toN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 which, when measured at about 25° C. with radiationat 1.54178 Å, is characterized by a powder diffraction pattern havingrespective 2θ values of about 6.70°, 10.1°, 11.8°, 13.40°, 14.40°,15.40°, 16.60°, 16.80°, 17.80°, 20.50° and 23.40°.

Another embodiment pertains to formulations comprising an excipient andN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 which, when measured at about 25° C. with radiationat 1.54178 Å, is characterized by a powder diffraction pattern havingrespective 2θ values of about 6.70°, 10.1°, 11.8°, 13.40°, 14.40°,15.40°, 16.60°, 16.80°, 17.80°, 20.50° and 23.40°.

Still another embodiment pertains to methods of treating cancer in amammal comprising administering thereto, with or without one or morethan one additional anticancer drugs, a therapeutically effective amountofN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 which, when measured at about 25° C. with radiationat 1.54178 Å, is characterized by a powder diffraction pattern havingrespective 2θ values of about 6.7°, 10.1°, 11.8°, 13.40°, 14.40°,15.40°, 16.60°, 16.80°, 17.8°, 20.5° and 23.4°.

Still another embodiment pertains to a process for makingN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 comprising:

providingN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaHydrate Crystalline Form 1; and

removing water from theN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaHydrate Crystalline Form 1 to formN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2.

Still another embodiment comprisesN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 prepared by the process of the preceding embodiment.

Still another embodiment comprises ABT-869 Tolueneate for use inpreparingN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2.

Still another embodiment comprises a salt of ABT-869 for use inpreparingN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2.

Still another embodiment comprises the hydrochloride salt of ABT-869 foruse in preparingN-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder x-ray diffraction pattern forN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2.

DETAILED DESCRIPTION OF THE INVENTION

This invention pertains to discovery ofN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2, ways to make it, ways to characterize it,formulations containing it and made with it, and methods of treatingcancer using it. The terms“N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea”and “ABT-869” are meant to be used interchangeably.

The terms “ABT-869” and “an ABT-869” without any indicia ofcrystallinity or non-crystallinity associated with it, as used herein,mean amorphous ABT-869, a crystalline ABT-869, microcrystalline ABT-869,ABT-869 in solution, a semisolid, wax or oil form of ABT-869, mixturesthereof and the like.

The terms “crystalline” and “microcrystalline,” as used herein, meanhaving a regularly repeating arrangement of molecules which ismaintained over a long range or external face planes.

Unless stated otherwise, percentages herein are weight/weight (w/w)percentages.

The term “hydrochloride salt,” as used herein, means having associatedtherewith one or more than one hydrochloride equivalent.

The term “solvent,” as used herein, means a liquid in which a compoundis soluble or partially soluble enough at a given concentration todissolve or partially dissolve the compound.

The term “anti-solvent,” as used herein, means a liquid in which acompound is insoluble enough at a given concentration to be effectivefor precipitating that compound from a solution.

Solvents and anti-solvents may be mixed with or without separation ofphases.

It is meant to be understood that, because many solvents andanti-solvents contain impurities, the level of impurities in solventsand anti-solvents for the practice of this invention, if present, are ata low enough concentration that they do not interfere with the intendeduse of the solvent in which they are present.

The term “acid,” as used herein, means a compound having at least oneacidic proton. Examples of acids for the practice of this inventioninclude, but are not limited to, hydrochloric acid, hydrobromic acid,trifluoroacetic acid, trichloroacetic acid, sulfuric acid, phosphoricacid and the like.

The term “base,” as used herein, means a compound capable of accepting aproton. Examples of bases for the practice of this invention include,but are not limited to, sodium carbonate, sodium bicarbonate, potassiumcarbonate, potassium bicarbonate, dibasic sodium phosphate (i.e.Na₂HPO₄, K₂HPO₄ and the like), triethylamine, diisopropylethylamine andthe like.

The term “isolating” as used herein, means separating ABT-869Crystalline Form 2 from solvent, anti-solvent, or a mixture of solventanti-solvent. This is typically accomplished by means such ascentrifugation, filtration with or without vacuum, filtration withpositive pressure, distillation, evaporation or a combination thereof.

Therapeutically acceptable amounts of ABT-869 Crystalline Form 2 dependon recipient of treatment, disorder being treated and severity thereof,composition containing it, time of administration, route ofadministration, duration of treatment, its potency, its rate ofclearance and whether or not another drug is co-administered. The amountof ABT-869 Crystalline Form 2 used to make a formulation to beadministered daily to a patient in a single dose or in divided doses isfrom about 0.03 to about 200 mg/kg body weight. Single dose formulationscontain these amounts or a combination of submultiples thereof.

ABT-869 Crystalline Form 2 may be administered with or without anexcipient, typically with an excipient. Excipients include but are notlimited to, for example, encapsulating materials and additives such asabsorption accelerators, antioxidants, binders, buffers, carriers,coating agents, coloring agents, diluents, disintegrating agents,emulsifiers, extenders, fillers, flavoring agents, glidants, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents, mixturesthereof and the like.

Excipients for preparation of formulations comprising or made withABT-869 Crystalline Form 2 to be administered orally in solid dosageform include, for example, agar, alginic acid, aluminum hydroxide,benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castoroil, cellulose, cellulose acetate, cocoa butter, copovidone, cornstarch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol,ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters,gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide,magnesium stearate, malt, mannitol, monoglycerides, olive oil, povidone,peanut oil, potassium phosphate salts, potato starch, povidone,propylene glycol, Ringer's solution, safflower oil, sesame oil, silicondioxide, sodium carboxymethyl cellulose, sodium phosphate salts, sodiumlauryl sulfate, sodium sorbitol, sodium stearylfumarate, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, vitamin E and derivativesthereof, water, mixtures thereof and the like.

Excipients for preparation of formulations comprising or made withABT-869 Crystalline Form 2 to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water, mixtures thereof and thelike.

Excipients for preparation of formulations comprising or made withABT-869 Crystalline Form 2 to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water, mixtures thereof andthe like.

Excipients for preparation of formulations comprising or made withABT-869 Crystalline Form 2 to be administered parenterally include, forexample, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose,germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water, mixtures thereof and the like.

Excipients for preparation of formulations comprising or made withABT-869 Crystalline Form 2 to be administered rectally or vaginallyinclude, but are not limited to, cocoa butter, polyethylene glycol, wax,mixtures thereof and the like.

ABT-869 Crystalline Form 2 is also useful when administered withanticancer drugs such as alkylating agents, angiogenesis inhibitors,antibodies, antimetabolites, antimitotics, antiproliferatives, aurorakinase inhibitors, Bcr-Abl kinase inhibitors, biologic responsemodifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors,cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2)receptor inhibitors, growth factor inhibitors, heat shock protein(HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonaltherapies, immunologicals, intercalating antibiotics, other kinaseinhibitors, including other PTKs, mammalian target of rapamycininhibitors, mitogen-activated extracellular signal-regulated kinaseinhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), platinumchemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors,purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids/deltoids plant alkaloids, topoisomerase inhibitors and thelike.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, Cloretazine™ (VNP 40101M), cyclophosphamide, decarbazine,estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine(CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine,nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa,treosulfan, trofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and thelike.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her21gG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®,NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam) ibuprofen cream, ALEVEL® andNAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin),CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL®(ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin),eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen(pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034),(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap,vatalanib, ZACTIMA™ (vandetanib, ZD-6474) and the like.

Antimetabolites include ALIMTAR® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR,enocitabine, ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil(5-FU) alone or in combination with leucovorin, GEMZAR® (gemcitabine),hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurineriboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed,ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine,trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and thelike.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (doxorubicin), elsamitrucin, epirbucin,glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarubicin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGFIR-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzumab and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), fadrozole,FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole),formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL®(sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE®(megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b), or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab,molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim),OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®,sargaramostim, sizofilan, teceleukin, TheraCys®, ubenimex, VIRULIZIN®,Z-100, WF-10, PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX®(daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like.

Compounds of the present invention are also intended to be used as aradiosensitizer that enhances the efficacy of radiotherapy. Examples ofradiotherapy include, but are not limited to, external beamradiotherapy, teletherapy, brachytherapy and sealed and unsealed sourceradiotherapy.

Additionally, ABT-869 Crystalline Form 2 may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN®, ALTOCOR® or MEVACOR® (lovastatin),AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN™ (exisulind),AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotene), AVE-8062,BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor),canvaxin (vaccine), CeaVac™ (cancer vaccine), CELEUK® (celmoleukin),CEPLENE® (histamine dihydrochloride), CERVARIX™ (human papillomavirusvaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CyPat™,combrestatin A4P, DAB(389)EGF or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906, GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16,18) recombinant vaccine), GASTRIMMUNE™ (gastrin-diptheria conjugate),GENASENSE™ (oblimersen sodium), GMK (ganglioside conjugate vaccine),GVAX® (prostate cancer vaccine), halofuginone, histerelin,hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR(cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-α,interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib,5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine),NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT®(pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanomavaccine treatment), OncoVAX (IL-2 Vaccine), ORATHECIN™ (rubitecan),OSIDEM® (antibody-based cell drug), OvaRex® MAb (murine monoclonalantibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginsengcomprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol(aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine),pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat,REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral),SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine(Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), Taxoprexin® (DHA-paclitaxel), TELCYTA™ (TLK286),temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide,THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFerade™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa(zolendronic acid), zorubicin and the like.

It is also expected that ABT-869 Crystalline Form 2 would inhibit growthof cells derived from a pediatric cancer or neoplasm including embryonalrhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatricacute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma,pediatric anaplastic ependymoma, pediatric anaplastic large celllymphoma, pediatric anaplastic medulloblastoma, pediatric atypicalteratoid/rhabdoid tumor of the central nervous system, pediatricbiphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatriccancers of Ewing's family of tumors such as primitive neuroectodermalrumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorablehistology Wilm's tumor, pediatric glioblastoma, pediatricmedulloblastoma, pediatric neuroblastoma, pediatricneuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers(such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidneytumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such aslymphoma and skin cancer and the like.

Preparation of ABT-869 and its utility as a PTK inhibitor is describedin commonly-owned U.S. Pat. No. 7,297,709.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention.

EXAMPLE 1 Preparation of ABT-869·¼ Ethanolate Crystalline Form 1

A mixture of ABT-869 hydrochloride in ethyl acetate and ethanol, inwhich the ABT-869 hydrochloride was completely soluble, was mixed withdibasic sodium phosphate. The organic layer was separated, treated withdecolorizing carbon, and filtered. A small quantity of L-ascorbic acidwas added, and the solution was concentrated. The ethyl acetate wasremoved by azeotropic distillation with ethanol. Additional ethanol maybe added and the solution heated to dissolve any solid that forms. Thesolution was cooled to 25° C. and diluted with water, causing ABT-869·¼Ethanolate Crystalline Form 1 to crystallize. The product was isolated,washed with water, and dried under reduced pressure, while monitoringresidual ethyl acetate and ethanol (by gas chromatography (GC)) andwater (by Karl Fischer (KF)). A yield of 92% is typical.

EXAMPLE 2 Preparation of ABT-869 Hydrate Crystalline Form 1

Following the neutralization with dibasic sodium phosphate, decolorizingcarbon treatment and the removal of ethyl acetate as described inEXAMPLE 1, the mixture of ABT-869 in ethanol was gradually mixed withwater at 25° C., with vigorous agitation. ABT-869.H₂O Crystalline Form 1was isolated, washed with water, and dried under reduced pressure whilemonitoring residual ethyl acetate and ethanol (by GC) and water (by KF).The dried material may be delumped/milled to control particle size. Ayield of 76% is typical.

EXAMPLE 3 Preparation of ABT-869 Crystalline Form 2

A mixture of EXAMPLE 2 was stored under nitrogen at 0% humidity.

Diffraction patterns were collected using an Inel G3000 diffractometerequipped with an incident beam germanium monochromator to provideCu—K_(α) ₁ radiation. The X-ray generator was operated at a voltage of40 kV and a current of 30 mA. The Inel G3000 is equipped with a positionsensitive detector that monitors all diffraction data simultaneously.The detector was calibrated by collecting the attenuated direct beam forseven seconds in 1 degree intervals across a 90 degree two theta range.The calibration was checked against a silicon line position referencestandard (NIST 640c). Powder X-ray diffraction (PXRD) analysis wasconducted in the following manner. A sample of hydrate powder was placedin a thin layer on the sample holder and gently flattened with a glassmicroscope slide. The hydrate sample was then equilibrated under drynitrogen purge at atmospheric temperature and pressure using the lowtemperature furnace for the Inel G3000 powder X-ray diffractometer. Thelow temperature furnace contains a Kapton® window that results in abroad diffraction peak at approximately 6 degrees two theta. The samplewas equilibrated under nitrogen overnight, followed by PXRD dataacquisition for two hours under continued nitrogen purge.

FIG. 1 is a powder x-ray diffraction pattern for this Crystalline Form2.

It is meant to be understood that relative intensities of peak heightsand/or intensities in a PXRD pattern may vary and will be dependent onvariables such as the temperature, size of crystal size or morphology,sample preparation, or sample height in the analysis well of the X-raydiffractometer.

It is also meant to be understood that peak positions may vary whenmeasured with different radiation sources. For example, Cu—K_(α) ₁ ,Mo—Kα, Co—Kα and Fe—Kα radiation, having wavelengths of 1.54060 Å,0.7107 Å, 1.7902 Å and 1.9373 Å, respectively, may provide peakpositions which differ from those measured with Cu—Kα radiation, whichhas a wavelength of 1.5478 Å.

The term “about” preceding a series of peak positions means that all ofthe peaks of the group which it precedes are reported in terms ofangular positions (two theta) with an allowable variability of ±0.1° asspecified by the U.S. Pharmacopeia, pages 1843-1884 (1995). Thevariability of ±0.1° is intended to be used when comparing two powderX-ray diffraction patterns. In practice, if a diffraction pattern peakfrom one pattern is assigned a range of angular positions (two theta)which is the measured peak position ±0.1° and if those ranges of peakpositions overlap, then the two peaks are considered to have the sameangular position. For example, if a peak from one pattern is determinedto have a position of 11.0°, for comparison purposes the allowablevariability allows the peak to be assigned a position in the range of10.9.°-11.1°.

Accordingly, for example, the phrase “about 6.7°, 10.1°, 11.8°, 13.40,14.40°, 15.40°, 16.6°, 16.8°, 17.8°, 20.5° and 23.4° means about 6.7°,about 10.1°, about 11.8°, about 13.4°, about 14.4°, about 15.4°, about16.6°, about 16.8°, about 17.8°, about 20.5° and about 23.4°, which, inturn, means 6.7°±0.1°, 10.1°±0.1°, 11.8°±0.1°, 13.4°±0.1°, 14.4°±0.1°,15.4°±0.1°, 16.6°±0.1°, 16.8°±0.1°, 17.8°±0.1°, 20.5°±0.1°, and23.4°±0.1°.

The term “about” preceding a temperature means the given temperature ±2°C. For example, about 25° C. means 25° C.±2° C. or 23° C.-27° C.

The foregoing is meant to be illustrative of the invention and notintended to limit it to the disclosed embodiments. Variations andchanges obvious to one skilled in the art are intended to be within thescope and nature of the invention as defined in the claims.

1.N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaCrystalline Form 2 which, when measured at about 25° C. with radiationat 1.54178 Å, is characterized by a powder diffraction pattern havingrespective 2θ values of about 6.7°, 10.1°, 11.8°, 13.4°, 14.40°, 15.4°,16.6°, 16.8°, 17.8°, 20.5° and 23.4°.